3D-QSAR, molecular docking, and dynamics simulation of quinazoline–phosphoramidate mustard conjugates as EGFR inhibitor

ABSTRACT

To develop novel and more potent quinazoline–phosphoramidate mustard conjugates as epidermal growth factorreceptor (EGFR) inhibitor, three-dimensional quantitative structure-activity relationship [comparative molecularfield analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)] combined with moleculardocking were performed. A series of 13 compounds in the training set gave q2 values of 0.577 and 0.537, as well as r2values of 0.926 and 0.921 for CoMFA and CoMSIA models, respectively. The contour maps that were produced by theCoMFA and CoMSIA models revealed that steric, electrostatic, and hydrophobic fields were crucial in the inhibitoryactivity of quinazoline–phosphoramidate derivatives. Based on the CoMFA and CoMSIA models, several novel EGFRinhibitors were designed, which established crucial interactions at the ligand binding domain of EGFR. Nearly, 100ns MD simulation indicated the stability of the designed compounds at 100 ns, while molecular mechanics-PoissonBoltzmann surface area calculation showed that the designed compound had a higher affinity than that of the parentcompound.